Adverse pregnancy outcomes in systemic lupus erythematosus: Special emphasis on biomarker reference intervals
Muna Saleh
Oct 2024 · Linköping University Electronic Press
Ebook
118
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Abstract: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology, characterized by a wide range of manifestations that can vary from mild to severe or even life-threatening multiple organ system involvement. SLE predominantly affects women and has a peak incidence during women’s reproductive age. Given the complexity of SLE, managing pregnancy in these women is particularly challenging, as the disease itself can impact pregnancy outcomes, and conversely, pregnancy can exacerbate SLE symptoms. This thesis aims to explore pregnancy complications among women with SLE and to assess the feasibility of utilizing specific biomarkers for evaluating the risk of adverse outcomes in SLE pregnancies, as well as their potential to predict these outcomes. Paper I: A descriptive study on adverse pregnancy outcomes (APOs) in a Swedish population was conducted, involving 28 women diagnosed with SLE and 59 pregnancies monitored from 2002 to 2018 at Skåne University Hospital. The study aimed to determine the prevalence of each APO and to assess demographic, clinical, and laboratory risk factors. Most pregnancies experienced at least one APO, although only a small number were categorized as severe. It was shown that a history of lupus nephritis was the clinical feature most strongly associated with APOs. Moreover, the co-occurrence of SLE and antiphospholipid syndrome was linked to an increased risk of miscarriage, and the presence of one or more antiphospholipid antibodies was correlated with APOs overall. In papers II and III, the aim was to investigate, in 100 healthy women with 100 normal pregnancies selected from the pregnancy register and biobank at Linköping University (GRABB), if pregnancy influences the normal reference values of biomarkers such as complement proteins and pentraxins, to establish a reference interval that is more appropriate for the pregnancy period. Paper II: This study investigated the complement system, which is a vital component of the humoral innate immune system that exhibits increased activity during pregnancy. This function is necessary for maintaining the host's defense and ensuring fetal survival. However, excessive or unbalanced activation of the complement system in the placenta has been linked to various APOs. The study found that maternal plasma C1q and the C3d/C3 ratio had their highest mean values during the first trimester, while C3, C4, and C3d levels increased until delivery. However, the reference limits for complement analyses used for the general population were generally suitable for most of the samples in the study. This suggests that while there were some deviations from the norm in complement levels in certain pregnant women, the standard reference values still adequately captured the overall trends in complement activity during pregnancy in this population. Paper III: This study investigated the same population as in paper II and focused on two types of pentraxins: the liver-produced short pentraxin C-reactive protein (CRP), which is commonly used in clinical practice, and the leukocyte-produced long pentraxin 3 (PTX3), which is structurally and functionally related to CRP. Both pentraxins were previously described as biomarkers related to various APOs. The study found that both CRP and PTX3 levels were significantly elevated in the third trimester compared to the other trimesters. This suggests that during pregnancy, particularly in the later stages, reference values for these biomarkers may need to be adjusted to account for these physiological changes, highlighting the importance of considering pregnancy-specific reference values for these markers. Paper IV: Plasma levels of CRP, PTX3, C3, and C4 were assessed during 123 pregnancies in 102 patients with SLE and 170 pregnancies in women from the general population concerning the risk of APOs. All the patients and controls were recruited from three Swedish cohorts: the Lund cohort, referenced in Paper I; the GRABB cohort, which is mentioned in Papers II and III; and the SLE-Placenta cohort (SLE-PLAC) which is a multicenter Swedish cohort. Only PTX3 showed higher levels in the first and third trimesters of SLE pregnancies with APOs. Even after including control pregnancies with APOs, PTX3 levels remained significantly higher in complicated pregnancies, suggesting that PTX3 could serve as a potential biomarker for identifying at-risk complicated pregnancies.
Conclusion: The incidence of APOs in pregnancies affected by SLE is significantly higher than in the general population, highlighting the urgent need for risk stratification and increased attention to specific clinical and serological risk factors in these cases. It is essential to note that reference intervals for some biomarkers may require adjustment during the pregnancy period to ensure accurate interpretation. While our findings need to be confirmed, the pentraxins especially PTX3 could be used for the risk stratification of pregnant women with SLE.
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